The objective of this proposal is to investigate the mechanisms underlying the preferential uptake and sequestration of a variety of compounds by the lung. Preliminary results show that preexposure of rabbits to aerosolized piperonyl butoxide (8 ppm, 30 min, 24 hr post exposure) results in marked enhancement of (120 percent) lung uptake of the tricyclic antidepressant imipramine. Pretreatment with bisolvon, a quanternary ammonium compound used as a stimulant of surfactant formation in certain cases of atelectasis, results in more numerous and enlarged concentric lamellar bodies in the adveolar type II cells. Isolated perfused lung preparations from bisolvon treated animals retained markedly higher concentrations of imipramine. The increased lysosomal secretory organelles and the elevated levels of phospholipid content coincidental with the enhanced drug sequestration suggest a possible relationship between lung phospholipids and a number of amphiphilic drugs known to be preferentially accumulated by the lung. The piperonyl butoxide treatment model and the drug induced pulmonary lipidosis model will be utilized in investigations directed at understanding the mechanisms underlying the pulmonary accumulation of drugs. Results of the drug uptake studies with imipramine, cyclizine and phentermine, etc., will be compared with their chlorinated analogs, viz. clomipramine, chlorcyclizine, and chlorphentermine, etc., respectively, in control as well as the drug pretreatment models. Investigations will include studies on the displacement of a previously sequestered drug following uptake of another xenobiotic by the lung. Understanding the basic mechanisms governing the preferential sequestration and release of drugs by the lung are essential in clinical management of significant drug interactions attributable to drug storage in the pulmonary tissue.